Aza-Michael Quaternization: Addition of Tertiary Amines to Allenic Michael Acceptors Furnishes Quaternary Ammonium...

The aza-Michael addition is a widely employed carbon-nitrogen bond-forming "click" reaction that is commonly utilized for the addition of primary and secondary amines. The aza-Michael addition of tertiary amines, however, is rarely observed. The prospective products of this reaction, quaternary ammonium compounds (QACs), have become an important and extensively utilized and researched class of chemicals. Yet, to this day, QACs are almost exclusively prepared through the nucleophilic substitution reaction between amines and classical alkylating agents. Herein, we introduce the aza-Michael addition of tertiary amines to allenic Michael acceptors as an alternative and versatile approach to preparing QACs, termed aza-Michael quaternization. The aza-Michael quaternization provides a general strategy that is amenable to a variety of chemically diverse tertiary amines and electron-deficient allenic substrates. The reaction proceeds fastest in green solvents and exhibits chemoselectivity in the presence of a wide range of functionalities, including common peptide side chains other than cysteine. Employing DFT calculations, the reaction pathway is elucidated, highlighting the importance of the additional resonance stabilization offered by the allene functionality and also explaining the reaction's high selectivity for tertiary amines.